The National Heart, Lung, and Blood Institute (NHLBI) recently held a pre-application information forum for investigators planning to submit applications in response to RFA HL-01-015, “Comprehensive Sickle Cell Centers.”  This public information  forum was held at the site of the 42nd Annual Meeting of the American Society of Hematology (ASH), at the Sheraton Palace Hotel, Sea Cliff Room, in San Francisco, CA, on December 1, 2000, from 7:00- 8:30 PM.  The forum began with a detailed presentation by NHLBI staff of the structure of the new Comprehensive Sickle Cell Center program that will begin in April, 2003. An interactive discussion session followed, and shown below, is a record of the questions asked by potential applicants, and answers given by NHLBI staff.  This record is intended for the benefit of the interested general public as well as for interested potential applicants who were unable to attend the public information forum. Approximately 75 individuals attended the forum and filled out registration forms on-site.

Applications for this RFA are due September 25, 2001, and the RFA solicitation document is available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-01-015.html.

Question 1: How was the annual budget cap for the clinical core of $400K total costs arrived at? This would seem to be an inadequate sum if it is to cover the cost of all personnel engaged in clinical research at that Center.

Answer: This sum is significantly greater than the current level of funding for clinical cores in the program, and was thought to be adequate to cover the dual functions of the clinical core: 1) providing patients the best current models of care; and 2) supporting all the personnel (principal investigator, nurse, data manager etc.) that will participate in inter-Center collaborative clinical (network) projects though that Center. Non-network clinical projects that are included in the cap have their own separate budgets for personnel. So it is not true that all personnel engaged in clinical research must be supported through the clinical core. This may be a point of confusion. Finally, this type of budget structure for clinical networks is based on other successful NHLBI models in existence- for example the existing Asthma-, Pediatric Cardiology-, and Thalassemia Clinical Research Networks.

Question 2: For the class of clinical project that is not included in the network, and is included in the budget cap, is the principal investigator’s salary covered in the clinical core?

Answer: No.  The principal investigator’s salary would be covered in the budget for that particular project, not in the clinical core. However, it is hoped that the clinical core through its patient care component would help to recruit patients for the hypothetical project you mention. So there should be some connection there.

Question 3: If a Center has a multi-Center clinical study it wants to propose, does this have to be proposed as a network project?

Answer: No. If a Center has arranged in advance to have several collaborators for a multi-Center study, then this study could be supported as a clinical project that comes under the budget cap. Again, to restate what was in the detailed program description just provided, there are two types of clinical projects in the new program. One is a network project, which is not wholly supported within the budget cap of a Center, and which is proposed as a concept for a multi-Center study where collaborators are not arranged in advance. The other is a clinical project that is wholly supported under the Center’s budget cap,and where collaborators may be arranged in advance. Having both mechanisms for clinical projects adds flexibility to this program.

Question 4: Will each Center that participates in the network automatically receive $360K per year for patient reimbursement?

Answer: No. This amount is just an estimate of the maximum available per Center for per-patient protocol reimbursement costs. It does not include personnel for the network projects. Personnel for network projects are supported separately through the clinical core, as mentioned previously (above). Specifically, this amount is one-tenth of the amount that will be available program-wide for per-patient protocol costs each year.

Question 5: Is there a negative penalty for large Centers that participate in a network project and contribute more patients than can be reimbursed by the available per-patient protocol reimbursement funds?

Answer: Yes and No.  If a Center had enrolled more patients than it could be reimbursed for, then in this sense it could be penalized to the extent that it would not be fully reimbursed for each patient. However, it is reasonable to think that this can be prevented with good communication between investigators, the NHLBI Project Scientist and Grants Management Specialist, and the Statistics and Data Management Center. It is also formally possible that more than $360K in protocol reimbursement funds can be directed to a single Center if that Center has enrolled more patients than other Centers and if the total program funds for per-patient reimbursement have not been completely disbursed for that grant year. Again, the $360K is just an estimate of the maximum available funds for network protocols, per Center, per year.

Question 6: Will the required and optional cores be assigned numerical scores during the merit review process?

Answer: No. All cores (clinical, patient service, administrative, and any optional laboratory cores) will either be recommended or not recommended for funding consideration. They will not receive a numerical score. This is the same way cores were reviewed in 1997, for the last competitive cycle for this program.

Question 7: Will there be site visits as part of the review process for the next competition?

Answer: No. The reason is that NHLBI does not currently include site visits in the review of any of its numerous programs. The elimination of site visits was a cost-saving measure implemented many years ago. While the NHLBI can appreciate how a site visit might give a better picture of an applicant’s abilities in the community outreach area, as it did in the early years of this program, to carry out site visits for this program it would somehow have to justify an exception to the policy of no site visits.

Question 8: Without review site visits, what is to prevent an applicant from putting on paper a better patient service core than will exist in reality?

Answer: NHLBI staff do not take for granted everything that is put on paper, and it is often possible to get a sense of whether something is realistic or not just by talking to people in the community.  Also, while there will be no site visits as part of the review, there definitely will be site visits by NHLBI staff to each center that is ultimately funded, and all activities will be evaluated on these visits.  NHLBI staff carry out these site visits even in the present funding cycle, but with the conversion of these Comprehensive Sickle Cell Center awards from grants to cooperative agreements in the new program, you can expect even more involvement by NHLBI staff in the activities of each Center.

Question 9: Will there be a separate RFA announcing priority topics for research projects to be proposed in Center applications?

Answer: No. Example topics are listed in this RFA for Comprehensive Sickle Cell Centers. There is only one RFA.

Question 10: In the next funding cycle, statistical services for all clinical and basic science research projects will be handled centrally in the Statistics and Data Management Center. How will access to statistical services be prioritized?

Answer: Prioritization of projects will not be up to the Statistics and Data Management Center alone. The resources of the Statistics and Data Management Center will be allocated based on input from the entire Steering Committee, which will have representatives from each Center. Clinical network projects will likely be given the highest priority. But remember that Statistics Center applicants will be evaluated in part on their ability to handle all the statistical needs of this complex program. So, you will be getting the best statisticians, and you will have input on project prioritization through your Steering Committee members.

Question 11: You have put more funding into the central Statistics and Data Management Center, at the apparent expense of funding for distributed local Statistics Cores.  Isn’t this a mistake, to have to work with one’s local statisticians to prepare an application, and then be forced to work with the central Statistics Center to implement a study after funding?

Answer: Having central statistical services was another cost-saving measure. A single, strong Statistics and Data Management Center is needed for our collaborative clinical studies, and it is possible for a central Statistics Center to serve the functions that would otherwise be served by a local Statistical Core. In a clinical network setting, it is believed this arrangement makes the most sense, and with this arrangement, the Statistics and Data Management Center will have to be involved with all the major studies going on across the program. This has clear advantages for coordination of efforts across the program, and for reporting to the NHLBI and the public at large. Your point about relying on local statistical support during the application process is a valid one, but central statistical support makes the most sense for clinical networks. Thus there is no way around this dilemma unless the statistical and clinical Centers were to be competed on a staggered schedule, so that a clinical Center could collaborate with the program’s statistical Center both during the application process and after funding. This is something to think about for the future.

Question 12: Do the proposals for inter-Center collaborative clinical projects (network projects) have to include budgets when submitted? How can this be if one does not know how many patients will be enrolled across the program, nor how many Centers will participate?

Answer: Yes, proposals for clinical network projects are expected to have budgets. These budgets will be estimates of the cost to implement the proposed multi-Center clinical study at the applicant’s Center only, based on costs for laboratory tests, drugs, and the estimated number of patients at that Center.

Question 13: Have the eligibility criteria for the Scholar program been changed to target young investigators with an interest in sickle cell disease research?

Answer: No, the criteria have not been changed since the previous competition. The slide I showed where it suggested that this program is targeted to young investigators reflects our hope that the Scholar program will train some younger investigators for future careers in sickle cell disease research. However, we cannot discriminate against more experienced investigators who have an interest in switching fields to take up sickle cell research. Thus this program is formally open to anyone who is working in a Comprehensive Sickle Cell Center environment, and who has at least two years of research experience past a professional degree.

Question 14: Are all of the requirements you listed on your slides absolutely required in the application at the time of submission?

Answer: Yes.

Question 15: You mentioned that mentors for sickle cell Scholars must be named in the career development writeup submitted with the application, but that Scholars can be named in the intervening period between application and funding. Does this mean that by the time of application, a Center must commit to recruiting a basic science-oriented versus clinically-oriented trainee?

Answer: Well, some cross-cutting physician-scientists could conceivably mentor a young scientist either in a basic science area or in a clinical area. So in this case, proposing a mentor would not necessarily commit to basic science versus clinical areas. However, it is probably true that most mentors will fall neatly into one category or the other, so yes, if only one mentor must be proposed at the time of application, in some cases the applicant is being asked to commit to one category of mentor or the other. Centers have some flexibility in designing their programs so many Centers may be more heavily weighted in the basic science versus clinical areas, and in this event, it may make some sense to train someone according to the main focus of that Center’s  program. The mentor must be the principal investigator of a subproject in a Center application, so there will not be a large number of mentor candidates to choose from. This seems to be a place where some flexibility may benefit the program, so NHLBI will consider whether it should be optional for Center applicants to name two mentors in the career development plans for Scholars- one mentor each in the basic science and clinical areas. Applicants can discuss this with NHLBI staff before submitting their applications.

Question 16: Does the mentor for the Scholar have to be the Center Director?

Answer: Not necessarily, but this is possible. The mentor must be the principal investigator of a subproject in a Center application, but need not be the Center Director.

Question 17: Will there be a possibility for non-NHLBI Centers, or foreign Centers to participate in the network projects?

Answer: Yes and No. The network budget infrastructure is not set up to support this on a routine ad hoc basis, but if the Steering Committee identified a valuable patient resource for a given protocol at a non-NHLBI site, then on a rare occasion it may be possible to include this site in a study. In addition, it is certainly possible for multiple institutions, including foreign ones, to be a part (through subcontracts) of the required clinical core of each Center. In this way, multiple clinical sites could participate in all network protocols through their parent Center.

Question 18: Does the Center Director have to be the principal investigator of a subproject?

Answer: Yes, this is a requirement.

Question 19: Does the Scholar career development plan required at the time of application have to identify a project or specify a research plan for the Scholar?

Answer: No. The Scholar candidate will be named, and the research plan will be submitted after the Center application is submitted. This will occur approximately 6 months before funding, but only for those applications in the funding range after the merit review.

Question 20: I would argue very vociferously for site visits. Centers that include Patient Service Cores and Clinical Cores can only be effectively evaluated with in-person site visits, where relationships between the various components of a Center can be evaluated. Other institutes at NIH recognize this, as site visits are still going on. Isn’t this a mistake to continue to exclude site visits in the review process?

Answer: As stated before, NHLBI discontinued site visits linked to reviews many years ago. NHLBI staff understand this argument and its associated concerns, but can only promise to take these comments back to NHLBI leadership for their consideration.

Question 21: In the case of a multi-Center study where a Center applicant has arranged to collaborate in advance with a second Center applicant, I assume both Centers would include this project in their applications?

Answer: Only one of the Centers need include this project in their application. The second site(s) can be listed as subcontractors. This project should not be included in identical form in more than one application. This would interfere with the independent evaluation of the potential of each applicant Center to meet the goals of the NHLBI Comprehensive Sickle Cell Center program. There are additional reasons not to do this which NHLBI staff can discuss with applicants at a later time.

Question 22: I am concerned about the extra responsibilities being added to the Statistics and Data Management Center. Specifically, applicants for this program component may not be qualified to set up a repository of patient samples, or collect information on quality-of-life issues faced by sickle cell patients. What was the thinking behind this?

Answer: The Statistics and Data Management Center will serve as the coordinating center for the whole program, in particular with respect to collaborative clinical studies. Applicants for this program component likely will have prior coordination experience with multi-Center clinical trials, and may have previous experience in setting up sample repositories as well. If such experience is not locally accessible, it will be incumbent upon the coordinating center applicant to find and include such expertise in their application. This program affords a special opportunity to collect samples for a sickle cell patient repository to be used for research purposes only, and the coordinating center is the logical choice to head this effort. This same argument applies to the collection of data on quality-of-life issues. This data is currently available nowhere, and this program provides a special opportunity to collect it and put it in user-friendly form. It is expected that each clinical center will cooperate with the coordinating center to provide this data, and the required data manager in each clinical core will provide the infrastructure to accomplish this.

Question 23: What are the chances that any one required clinical network proposal will be implemented?

Answer: We estimate that 1-2 protocols can be completed per year, and that 4-6 can be completed over the 5-year funding cycle. So, certainly most of the network proposals submitted by the 10 funded Centers will not be implemented in the first year. Only one or two protocols can win out early on. But the idea is that there will be a continuing prioritization process throughout the 5-year funding period, so that if a given protocol is not implemented in year 1, it may still be alive for consideration as a followup protocol in year 2 or later.

Question 24: Combining the requirements for clinical network activity and basic science research effectively exclude any community hospitals from participating in this program, because they can’t compete well in the basic science area. Is there any way that small community hospitals can participate in this program?

Answer: There has been an attempt in this new program to cast a wider net of participation by smaller clinical groups by encouraging the virtual center approach. This was done in part to address the very issue raised. In the virtual center model, the required clinical core can consist in fact of a consortium of clinics in different locations. These clinics would not be subject to any basic science requirements, so here is a way for community hospitals to fit in, if collaborative arrangements can be worked out with other sites that can meet the basic science requirements. It is certainly hoped that such collaborations can be formed.

Question 25: Given that there is an emphasis on virtual centers (consortium arrangements) in the new program, does this mean that virtual centers should have a scientific theme?

Answer: While there is no requirement to have a theme in a virtual center, an application that includes individuals doing complementary work in one thematic area of sickle cell disease research might be well received. However, a Center should propose to work in its historical area(s) of strength rather than completely switching gears to fit in with a theme that might be of great interest at the time.

Question 26: Is it true that network protocols will actually be limited to 1-2 years duration, and can the Steering Committee come up with protocols on its own rather than sticking strictly to what was proposed in Center applications?

Answer: The 1-2 year duration is just a guideline, to make it clear that very large and lengthy Phase III trials are not appropriate for this program. Yes, the Steering Committee can develop protocols that combine existing protocols from applicant Centers, or that are completely different. There are two reasons for requiring network proposals from each center applicant-one is to provide timely clinical research topics for the network, and the other is to evaluate the applicant’s ability to put together a feasible clinical research proposal, with a reasonable budget etc.

Question 27: Can you elaborate on the increased involvement of NHLBI staff in the new program, with the switch to the cooperative agreement mechanism?

Answer: This mechanism allows substantial involvement of NHLBI staff in a partner role. This level of involvement can be much greater than for a conventional R01 grant where involvement may be limited to review of an annual progress report. The NHLBI Project Scientist will sit on the Steering Committee that will meet several times a year, and will have a vote on matters put before that body. Staff will also likely participate in frequent conference calls. The NHLBI Project Scientist and Grants Management representative will also play key roles in evaluating requests for per-patient reimbursement, and seeing that these funds are distributed. NHLBI staff will definitely not be directing projects unilaterally in this program. NHLBI staff will be active partners.

Question 28: It makes more sense to me to have 7-8 network projects active at one time, rather than one or two, as was stated in your presentation. This would greatly facilitate recruitment of patients, if a patient recruited for one study could be made aware of other concurrent studies, and could either participate in the other studies or help spread the word about the existence of these other studies. Is this possible?

Answer: The statement about one or two protocols being active at one time is just a guideline. If your center is funded, and you can talk the Steering Committee into going in this direction, and there are sufficient funds available to support this, then this may be possible, especially in the later stages of the network’s development. However, it is questionable whether there will be sufficient funds to support this level of activity adequately. In addition, achievement of adequate accrual of patients for 7-8 ongoing clinical studies would be a daunting task, one perhaps less feasible than for 1-2 concurrent studies.

Question 29: I commend the increased priority being given to clinical research in sickle cell disease. However, I worry that it may not be possible to meet the apparent goal of completing network projects within 1-2 years. This is naive. It has taken us 6-8 months just to develop the study forms in the Thalassemia Clinical Network supported by NHLBI. Quality clinical research takes more time than this network arrangement may allow. I worry about this. Why the 1-2 year limit?

Answer: First of all, the goal of having each protocol be active for only 1-2 years is again just a guideline. It is not written in stone, and may be subject to some negotiation within the Steering Committee, if for example a more lengthy trial is deemed to be of unusual importance. However, this network is meant to provide a flexible infrastructure for small-scale clinical research, that can rapidly implement a Phase I/II protocol to provide preliminary safety and efficacy data. The idea is that the large Phase III trials will be done elsewhere when necessary, and will be based on the studies done by the network. To have this infrastructure available to answer new questions, it cannot have its resources committed to very lengthy trials. The network setting is not meant to support very lengthy or very costly trials. Neither the 5-year funding cycle, nor the budget committment are sufficient to support that.

Question 30: Does an application for the Statistics and Data Management Center have to be submitted as part of a Center application, as was the case in the last competition?

Answer: No. In the new program, the Statistics and Data Management Center applications are to be submitted separately.

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